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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The study plan was signed on 13 Nov 2018, and dosing was initiated on 15 Feb 2019. The in-life phase of the study was completed on 01 Mar 2019. The experimental start date was 14 Feb 2019, and the experimental completion date was 23 May 2019.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019

Materials and methods

Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
- Principle of test: The objectives of this 14-day pilot study (dose range finding study) was to examine whether the feeding of Cadmium telluride up to 100 mg/kg bw (1500 ppm) for 14 days was tolerated by Wistar Han rats and to provide data for the selection of the dose levels for a subsequent sub-chronic (90-day) oral toxicity study with Cadmium telluride. In addition, it was evaluated what the cadmium and tellurium concentrations in the liver and kidney were compared to when Cadmium chloride was being dosed.
- Parameters analysed / observed: clinical signs, body weights, food consumption, cadmium and tellurium concentrations in liver, kidney, urine and feces, gross necropsy findings and kidney and liver weights.
GLP compliance:
no
Remarks:
Palatability studies have a non-GLP status but are carried out in the quality assured environment of Charles River Den Bosch GLP test facility. No guidelines are applicable as this study is used for dose level selection purposes only.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
Batch (Lot) Number: CdTe #217824-B
Expiry date: 13 September 2020
Physical Description: Black powder
Purity/Composition: 99.999 %
Storage Conditions: At room temperature
Test item handling: No specific handling conditions required
Stability at higher temperatures: Stable

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
Han
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 6 weeks old
- Weight at study initiation: between 127 and 147 g
- Housing: animals were group housed (up to 3 animals of the same sex and same dosing group together) in polycarbonate cages (Makrolon type IV, height 18 cm or Makrolon type 2000P, height 21.5 cm) containing appropriate bedding (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles.
- Diet (e.g. ad libitum): ad libitum; Diet was provided ad libitum in stainless steel containers, covered by a stainless steel grid to prevent spillage, except during designated procedures. Diets remained in the food hopper for a maximum of one day, and on the day of weighing the remaining food in the food hopper was replaced with new diet. Food hoppers were shaken on a daily basis to divide any sawdust equally over the diet in order to facilitate food consumption. The feed was analyzed by the supplier for nutritional components and environmental contaminants. Results of the analysis were provided by the supplier and are on file at the Test Facility. It is considered that there were no known contaminants in the feed that would interfere with the objectives of the study.
- Water (e.g. ad libitum): Municipal tap water was freely available to each animal via water bottles. Periodic analysis of the water is performed, and results of these analyses are on file at the Test Facility. It is considered that there are no known contaminants in the water that would interfere with the objectives of the study.
- Acclimation period: The animals were allowed to acclimate to the Test Facility toxicology accommodation for 8 days before the commencement of dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 20
- Humidity (%): 48 to 50
- Air changes (per hr): en or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.
- Photoperiod (hrs dark / hrs light):12 hour light/12 hour dark

IN-LIFE DATES: From: 14 Feb 2019 To: 1 March 2019

Administration / exposure

Route of administration:
oral: feed
Details on route of administration:
The oral route of exposure via dietary inclusion was selected because this is a possible route of human exposure during manufacture, handling or use of the test item.
The dose levels were selected based on information provided by the Sponsor, and designed to follow the method described in Loeser and Lorke, 1977: Toxicology 7: 215-224. The high-dose level should not produce toxic effects, nor excessive lethality that would prevent meaningful evaluation. The mid-dose level is expected to produce no toxic effects.
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
The test item and reference item were mixed without the use of a vehicle, a premix was prepared to gradually mix the test item with the required amount of powder feed. Standard powder rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) were used. Diets were prepared for use at room temperature for the whole study. Diets were kept in daily aliquots at room temperature until use, if not used on the day of preparation.

Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Analysis of test item in diet for concentration, stability, homogeneity was not performed, however, to limit the impact, the dietary preparation was performed with approved procedures and documented in detail. Diets were visually inspected for homogeneity prior to use.
Concentration and homogeneity analyses performed previously in conjunction with the method development and validation study (Test Facility Study No. 20170592) demonstrated that the test item is homogeneously distributed in the diet when prepared under the same conditions at concentrations bracketing those used in the present study.
Duration of treatment / exposure:
14 days, oral feed exposure
Frequency of treatment:
food ad libitum
Doses / concentrationsopen allclose all
Dose / conc.:
750 ppm
Remarks:
equals 50 mg/kg bw/day
Dose / conc.:
1 500 ppm
Remarks:
equals 100 mg/kg bw/day
No. of animals per sex per dose:
3
Control animals:
yes
Details on study design:
- Dose selection rationale: The dose levels were selected based on information provided by the Sponsor, and designed to follow the method described in Loeser and Lorke, 1977: Toxicology 7: 215-224. The high-dose level should not produce toxic effects, nor excessive lethality that would prevent meaningful evaluation. The mid-dose level is expected to produce no toxic effects.
one reference dose group was used to be able to compare the cadmium concentrations in liver and kidney to the results described in Loeser and Lorke, 1977: Toxicology 7: 215-224 using Cadmium chloride.
- Rationale for animal assignment (if not random): randomization
- Fasting period before bioanalytical sampling colletion: approximately 18 hours
Positive control:
CdCl2 in the diet: 30 ppm (equals 2mg/kg bw/day)

Examinations

Observations and examinations performed and frequency:
MORTALITY/MORIBUNDITY CHECKS: Yes.
Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day. Animals were not removed from the cage during observation, unless necessary for identification or confirmation of possible findings.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical observations were performed once daily, beginning during the first administration of the test item and lasting throughout the Dosing Period.
The time of onset, grade and duration of any observed sign was recorded. Signs were graded for severity and the maximum grade was predefined at 1, 3 or 4. Grades were coded as slight (grade 1), moderate (grade 2), severe (grade 3) and very severe (grade 4). For certain signs, only its presence (i.e. maximum grade 1) was scored. In the data tables, the scored grades were reported, as well as the percentage of animals affected in summary tables.


BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed individually twice weekly, starting on Day 1. A fasted weight was recorded on the day of necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Food consumption was quantitatively measured daily starting on Day 1 and continuing throughout the Dosing Period.

FOOD EFFICIENCY: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine:
Urine and feces samples were collected separately on melting ice into specimen vials from animals housed in individual metabolism cages overnight (approximately 18 hours) with absence of food, but water was available.
After collection, the total amount of urine was determined and samples were divided into two aliquots. Urine samples were transferred into micronic tubes and stored at ≤ -75°C until transfer on dry ice to the bioanalysis group (aliquot A, including ≥ 100 µL) or until possible future analysis (aliquot B, remnant).
The specimen vials used for the feces collection were weighed before and after feces collection to determine the exact amount of feces. Feces samples were stored at ≤ -75°C until transfer on dry ice to the bioanalysis group.
The bioanalytical laboratory was notified before shipment of the samples. Samples were stored at the bioanalytical laboratory at ≤ -75C.”

- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY:No

OTHER:

Organ weights: liver and kidney were weighed at necropsy. Paired organs were weighed together. In the event of gross abnormalities, in addition to the combined weight, the weight of the aberrant organ was taken and recorded in the raw data.

Urine and feces were collected from animals individually housed in metabolism cages for approximately 18 hours in the absence of food but presence of water. After collection all samples were transferred the appropriate laboratory for analysis.Urine, feces, kidney and liver samples were analyzed for concentration of cadmium and telluride using a validated analytical procedure of Testing Facility Study No. 20170598
Sacrifice and pathology:
GROSS PATHOLOGY: yes
Necropsy:
Animals were subjected to a complete necropsy examination, which included evaluation of the carcass and musculoskeletal system; all external surfaces and orifices; cranial cavity and external surfaces of the brain; and thoracic, abdominal, and pelvic cavities with their associated organs and tissues.
Necropsy procedures were performed by qualified personnel with appropriate training and experience in animal anatomy and gross pathology. A veterinary pathologist, or other suitably qualified person, was available.


HISTOPATHOLOGY: No
Statistics:
Descriptive statistics number, mean and standard deviation were reported whenever possible.
Body Weight Gains: Calculated against the body weight on Day 1.
Food Consumption Calculated between at least each scheduled interval.
Test Item Intake: Calculated as concentration of test item in diet against relative food consumption.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical signs were noted during daily detailed clinical observations.
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights and body weight gain of treated animals remained in the same range as controls over the study period.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption before or after correction for body weight was similar to the control level over the study period.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Description (incidence and severity):
Bioanalysis part of the study is still ongoing
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Organ weights and organ:body weight ratios of treated animals were considered to be similar to those of control animals.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment.
In the Reference Group, dark red foci of the glandular mucosa of the stomach were observed in one animal. This finding was considered to be of no toxicological significance, since it remained within the range of biological variation for rats of this age and strain.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 500 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
gross pathology

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the results of the tolerability study, administration of Cadmium telluride in diet was well tolerated in rats at levels up to 1500 ppm.
Executive summary:

The objectives of this 14-day pilot study (dose range finding study) was to examine whether the feeding of Cadmium telluride up to 100 mg/kg bw (1500 ppm) for14 days was tolerated by Wistar Han rats and to provide data for the selection of the dose levels for a subsequent sub-chronic (90-day) oral toxicity study with Cadmium telluride. In addition, it was evaluated what the cadmium and tellurium concentrations in the liver and kidney were compared to when Cadmium chloride was being dosed. 

The study design was as follows:


Experimental Design

Group No.

Test Item Id.

Dose Level

 (ppm)

Number of Animals

Females

1

Control

0

3

2

Cadmium telluride

750

3

3

Cadmium telluride

1500

3

Reference Group

Cadmium chloride

30

3

 

The following parameters and endpoints were evaluated in this study: clinical signs, body weights, food consumption, cadmium and tellurium concentrations in liver, kidney, urine and feces, gross necropsy findings and kidney and liver weights.

For the cadmium telluride groups and reference group (cadmium chloride), the following was concluded:

No mortality occurred during the study period.

No treatment-related clinical signs were noted during daily detailed clinical observations.

Body weights and body weight gain of treated animals remained in the same range as controls over the study period.

Food consumption before or after correction for body weight was similar to the control level over the study period.

Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment.

Organ weights and organ to body weight ratios of treated animals were considered to be similar to those of control animals.

Based on the results of the tolerability study,administration of Cadmium telluride in diet was well tolerated in rats at levels up to 1500 ppm.